Maternal microchimerism is prevalent in cord blood in memory T cells and other cell subsets, and persists post-transplant

Kanaan, Sami B; Gammill, Hilary S.; Harrington, Whitney E.; Rosa, Stephen C. De; Stevenson, Philip A.; Forsyth, Alexandra M.; Allen, Judith; Cousin, Emma; Besien, Koen van; Delaney, Colleen; Nelson, J. Lee

doi:10.1080/2162402x.2017.1311436

Cited by 42 publications

(65 citation statements)

References 46 publications

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“…1A). DERAA standard curves were generated as previously described (28) and run on background DNA (DERAA −/− ) at varying concentrations to determine optimal sensitivity. The DERAA qPCR assay could detect a single DNA target in a background of up to 60,000 human cell genome equivalent (gEq) per amplification well ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…S11A). DNA from PBMCs of these study subjects was tested in assays specific to HLA-DRB1*15/16, *03, *07, *08, DRB4*01, DQA1*01, *03, DQB1*02, *03, *04, *06, and B*44 or non-HLA polymorphisms in the GSTT1, TG, and ATIII genes in case HLA of the subject and the Mc source was indistinguishable (28,40). DERAA − /SE − Mc was significantly increased in patients vs. controls, and ranked values were significantly higher among RA women (Fig.…”

Section: Deraa-mc Data Are Not Correlated With Clinical Features Ormentioning

confidence: 99%

“…Mc of fetal origin is unique to women, and Mc with DERAA + HLA (DERAA-Mc) is compelling as an additional source driving molecular mimicry and explaining the paradoxical increase of RA when a child had DERAA in his/her HLA genotype. Mc occurs naturally as a result of fetal-maternal cell exchange (27), with long-term persistence of allogeneic cells including immunologically relevant cell types (28)(29)(30). These microchimeric cells express nonshared familial antigens with the potential for significant immunological Significance HLA genes confer the strongest genetic autoimmune disease risk.…”

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confidence: 99%

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Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism

Kanaan

Sensoy

Zhen

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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HLA class II genes provide the strongest genetic contribution to rheumatoid arthritis (RA). HLA-DRB1 alleles encoding the sequence DERAA are RA-protective. Paradoxically, RA risk is increased in women with DERAA+ children born prior to onset. We developed a sensitive qPCR assay specific for DERAA, and found 53% of DERAA−/− women with RA had microchimerism (Mc; pregnancy-derived allogeneic cells) carrying DERAA (DERAA-Mc) vs. 6% of healthy women. DERAA-Mc quantities correlated with an RA-risk genetic background including DERAA-binding HLA-DQ alleles, early RA onset, and aspects of RA severity. CD4+ T cells showed stronger response against DERAA+ vs. DERAA− allogeneic cell lines in vitro, in line with an immunogenic role of allogeneic DERAA. Results indicate a model where DERAA-Mc activates DERAA-directed T cells that are naturally present in DERAA−/− individuals and can have cross-reactivity against joint antigens. Moreover, we provide an explanation for the enigmatic observation that the same HLA sequence differentially affects RA risk through Mendelian inheritance vs. microchimeric cell acquisition.

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Section: Resultsmentioning

confidence: 99%

Section: Deraa-mc Data Are Not Correlated With Clinical Features Ormentioning

confidence: 99%

mentioning

confidence: 99%

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Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism

Kanaan

Sensoy

Zhen

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…It has also been noted that cord blood immune cell populations, including T-cells, B-cells, NK cells, and monocytes frequently include cells of maternal origin, which are particularly enriched among memory T-cells. 55 Although unproven, this raises the possibility that maternal-origin immune effector cells may directly contribute to the fetal immune defense against malaria and other pathogens.…”

Section: Pl Acental Mal Aria and Maternal Microchimeris Mmentioning

confidence: 99%

The immune response to malaria in utero

Feeney

2019

Immunological Reviews

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Malaria caused by Plasmodium falciparum is a leading killer of infants and children. Efforts to develop a protective vaccine have been hindered by the parasite's numerous evasion strategies, which include the induction of immunoregulatory mechanisms in the human host.Indeed, several promising vaccine candidates that induce robust protection in malaria-naive populations have been shown to have much lower efficacy when administered to individuals residing in endemic settings, 1,2 suggesting that immunomodulatory mechanisms induced by prior malaria exposure may pose a critical barrier to vaccine-mediated protection. In endemic regions, many individuals are first exposed to malaria in utero, when P. falciparum-infected red blood cells sequester in the placenta and parasite antigens cross the syncytiotrophoblast barrier, gaining entry into the fetal circulation.Therefore, even during the neonatal period, vaccination may be influenced by prior malaria exposure. Here, we examine the consequences of in utero antigen exposure for fetal immune development and postnatal immunity. The worldwide burden posed by malaria-related complications of pregnancy is profound. More than 125 million pregnancies occur annually in regions at risk for malaria transmission, 3 and one in four pregnant women in sub-Saharan Africa have evidence of infection with malaria at parturition. 4 Although most placental malaria (PM) infections are attributable to P. falciparum, recent evidence indicates that P.vivax is also associated with poor pregnancy outcomes, and some data suggest that it too may sequester in the placenta. 5,6 Pregnancy-associated malaria results in tremendous obstetrical and pediatric morbidity, AbstractMalaria causes tremendous early childhood morbidity and mortality, providing an urgent impetus for the development of a vaccine that is effective in neonates. However, the infant immune response to malaria may be influenced by events that occur well before birth. Placental malaria infection complicates one quarter of all pregnancies in Africa and frequently results in exposure of the fetus to malaria antigens in utero, while the immune system is still developing. Some data suggest that in utero exposure to malaria may induce immunologic tolerance that interferes with the development of protective immunity during childhood. More recently, however, a growing body of evidence suggests that fetal malaria exposure can prime highly functional malariaspecific T-and B-cells, which may contribute to postnatal protection from malaria. In utero exposure to malaria also impacts the activation and maturation of fetal antigen presenting cells and innate lymphocytes, which could have implications for global immunity in the infant. Here, we review recent advances in our understanding of how various components of the fetal immune system are altered by in utero exposure to malaria, discuss factors that may tilt the critical balance between tolerance and adaptive immunity, and consider the implications of these findings for malaria prevention strateg...

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“…At the time of delivery, studies have demonstrated detection of maternal cellular Mc in 40-70% of umbilical cord blood samples [7,8]. In a recent study, detection of MMc in cord blood was demonstrated in both memory and naïve T cells, B cells, NK cells, and monocytes, with particularly high concentrations in memory T cells [13]. There is limited data on the mechanism of transfer, but data for a humanized rat model found that the trafficking of maternal cells into the fetus was dependent upon integrin-mediated adhesion to the syncytiotrophoblast and a VEGF gradient across the placenta [14].…”

Section: Mmc: Shaping the Immune System Beginning In Fetal Lifementioning

confidence: 99%

Microchimerism: Defining and redefining the prepregnancy context – A review

Gammill

Harrington

2017

Placenta

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Bidirectional transplacental exchange characterizes human pregnancy. Cells exchanged between mother and fetus can durably persist as microchimerism and may have both short- and long-term consequences for the recipient. The amount, type, and persistence of microchimerism are influenced by obstetric characteristics, pregnancy complications, exposures to infection, and other factors. A reproductive-aged woman enters pregnancy harboring previously acquired microchimeric “grafts,” which may influence her preconception health and her subsequent pregnancy outcomes. Many questions remain to be answered about microchimerism with broad-ranging implications. This review will summarize key aspects of this field of research and propose important questions to be addressed moving forward.

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Maternal microchimerism is prevalent in cord blood in memory T cells and other cell subsets, and persists post-transplant

Cited by 42 publications

References 46 publications

Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism

Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism

The immune response to malaria in utero

Microchimerism: Defining and redefining the prepregnancy context – A review

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